Isobel D. Walker

Thrombophilia in pregnancy: a systematic review

Growing evidence suggests that thrombophilia is associated with venous thromboembolism (VTE) and adverse pregnancy outcomes. However, methodological limitations have made it difficult to obtain a clear overview of the overall risks. We conducted a systematic review to determine the risk of VTE and adverse pregnancy outcomes associated with thrombophilia in pregnancy. The effectiveness of prophylactic interventions during pregnancy was also evaluated. Major electronic databases were searched, relevant data abstracted and study quality assessed by two independent reviewers. Odds ratios (ORs) stratified by thrombophilia type were calculated for each outcome. A total of 79 studies were included in our review. The risks for individual thrombophilic defects were determined for VTE (ORs, 0·74–34·40); early pregnancy loss (ORs, 1·40–6·25); late pregnancy loss (ORs, 1·31–20·09); pre‐eclampsia (ORs, 1·37–3·49); placental abruption (ORs, 1·42–7·71) and intrauterine growth restriction (ORs, 1·24–2·92). Low‐dose aspirin plus heparin was the most effective in preventing pregnancy loss in thrombophilic women (OR, 1·62). Our findings confirm that women with thrombophilia are at risk of developing VTE and complications in pregnancy. However, despite the increase in relative risk, the absolute risk of VTE and adverse outcomes remains low. There is also a lack of controlled trials of antithrombotic intervention to prevent pregnancy complications. Thus, at present, universal screening for thrombophilia in pregnancy cannot be justified clinically.

Prevalence of antithrombin deficiency in the healthy population

. In a cohort of 9669 blood donors we have identified 16 cases of congenital AT deficiency (1 in 600) by way of family studies and AT gene analysis. Two donors had type I AT deficiency (prevalence 0.21 per 1000; 95% CI = 0.03/1000 to 0.75/1000), their families displaying a symptomatic phenotype. 14 donors had a type II deficiency (prevalence 1.45 per 1000; 95% CI = 0.79/1000 to 2.43/1000): one recurring and three unique mutations. None of these type II deficiencies appeared to confer a high thrombotic risk despite many of the affected individuals having experienced potentially prothrombotic challenges. The high frequency of these relatively asymptomatic variants may reflect a selection bias in the study population. However, their existence should not only add to our understanding of structure‐function relationships of AT but may also influence our management of asymptomatic deficient individuals identified in epidemiological or presurgical screening programmes.

Short- and Long-Term Changes in Plasma Inflammatory Markers Associated With Preeclampsia

Preeclampsia is characterized by hypertension, dyslipidemia, and increased systemic inflammatory response and has been associated with an increased maternal risk of cardiovascular disease later in life. Low-grade chronic inflammation is a risk factor for cardiovascular disease. This study examined changes in inflammatory markers prospectively during pregnancy, the current inflammatory status of women who had a pregnancy complicated by preeclampsia 20 years previously against matched controls, and the association between inflammatory genes and risk of preeclampsia in a case (n=106) control (n=212) study. In control pregnancies (n=34), mean interleukin-10 (IL-10) levels increased 38% (P=0.012) and tumor necrosis factor-&agr; (TNF-&agr;) by 33% (P=0.024) between the first and third trimesters. The mean preeclampsia group IL-10 and TNF-&agr; rose by 43% (P=0.013 and P=0.0065, respectively) from the first to the third trimester. In women with preeclampsia only, plasma IL-6 increased from the first to the third trimester (1.66 [2.04] to 2.94 [2.47] pg/mL; P=0.0004). Twenty years after the index pregnancy, women who had had preeclampsia demonstrated significantly higher IL-6 to IL-10 ratio (3.96 [6.07] versus 2.12 [1.89]; P=0.034) compared with a healthy index pregnancy 20 years previously, that persisted after adjustment for smoking and current body mass index. The IL-1&bgr; (C-511T), IL-6 (G-174C), TNF-&agr; (G-308A), E-selectin (S128R), intercellular adhesion molecule-1 (K469E), and C-reactive protein (C1059G) polymorphisms were not associated with risk of developing preeclampsia. In conclusion, preeclampsia is associated with short- and long-term changes in inflammatory status.

Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism: a systematic review The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study

Combined oral contraceptives, oral hormone replacement therapy and thrombophilias are recognised risk factors for venous thromboembolism in women. The objective of this study was to assess the risk of thromboembolism among women with thrombophilia who are taking oral contraceptives or hormone replacement therapy, conducting a systematic review and metaanalysis. Of 201 studies identified, only nine met the inclusion criteria. Seven studies included pre-menopausal women on oral contraceptives and two studies included peri-menopausal women on hormone replacement therapy. For oral contraceptive use, significant associations of the risk of venous thromboembolism were found in women with factor V Leiden (OR 15.62; 95%CI 8.66 to 28.15); deficiencies of antithrombin (OR 12.60; 95%CI 1.37 to 115.79), protein C (OR 6.33; 95%CI 1.68 to 23.87), or protein S (OR 4.88; 95%CI 1.39 to 17.10), elevated levels of factor VIIIc (OR 8.80; 95%CI 4.13 to 18.75); and factor V Leiden and prothrombin G20210A (OR 7.85; 95%CI 1.65 to 37.41). For hormone replacement therapy, a significant association was found in women with factor V Leiden (OR 13.16; 95%CI 4.28 to 40.47). Although limited by the small number of studies, the findings of this study support the presence of interaction between thrombophilia and venous thromboembolism among women taking oral contraceptives. However, further studies are required to establish with greater confidence the associations of these, and other, thrombophilias with venous thromboembolism among hormone users.

Screening for thrombophilia in high-risk situations: a meta-analysis and cost-effectiveness analysis

Laboratory testing for the identification of heritable thrombophilia in high‐risk patient groups have become common practice; however, indiscriminate testing of all patients is unjustified. The objective of this study was to evaluate the cost‐effectiveness of universal and selective history‐based thrombophilia screening relative to no screening, from the perspective of the UK National Health Service, in women prior to prescribing combined oral contraceptives and hormone replacement therapy, women during pregnancy and patients prior to major orthopaedic surgery. A decision analysis model was developed, and data from meta‐analysis, the literature and two Delphi studies were incorporated in the model. Incremental cost‐effectiveness ratios (ICERs) for screening compared with no screening was calculated for each patient group. Of all the patient groups evaluated, universal screening of women prior to prescribing hormone replacement therapy was the most cost‐effective (ICER £6824). In contrast, universal screening of women prior to prescribing combined oral contraceptives was the least cost‐effective strategy (ICER £202 402). Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism was more cost‐effective than universal screening in all the patient groups evaluated.

Thrombophilia in pregnancy

Thrombophilia can be defined as a predisposition to thrombosis. Abnormalities in haemostasis that are associated with clinical thrombophilia include heritable defects, such as mutations in the genes encoding the natural anticoagulants antithrombin, protein C, and protein S, or clotting factors prothrombin and factor V, and acquired defects, such as antiphospholipids. Women with thrombophilic defects have been shown to be at increased risk, not only of pregnancy associated thromboembolism, but also of other vascular complications of pregnancy, including pre-eclampsia and fetal loss. Routine thrombophilia screening of all women attending antenatal clinics is not recommended. Because some thrombophilic defects—for example, type 1 antithrombin deficiency and antiphospholipids—are associated with a high risk of recurrent thrombosis or other pregnancy complications, it is suggested that selected women (those with a personal or confirmed family history of venous thromboembolism or with a history of recurrent fetal loss) are screened for these defects to allow pregnancy management planning.

Quality Assurance and Quality Control of Thrombelastography and Rotational Thromboelastometry: The UK NEQAS for Blood Coagulation Experience

Global hemostasis devices are currently being employed in operating rooms to assess the bleeding risk and outcomes for patients undergoing surgery. Two devices currently available are the TEG (Thromboelastograph; Haemoscope Corp., Niles, IL) and the ROTEM (Rotation Thromboelastometer; Pentapharm GmbH, Munich, Germany). Both measure the speed of clot formation, the strength of the clot when formed, and clot fibrinolysis kinetics. The two devices use different parameters so no cross comparisons of results can be made. The devices are usually operated by a member of the operating team and not a laboratory scientist; thus their testing and performance is generally not laboratory controlled, despite quality control being required to ensure reliable results. The UK National External Quality Assessment Scheme (NEQAS) for Blood Coagulation has undertaken a series of exercises evaluating the provision of External Quality Assessment (EQA) material for these devices. A series of four studies have taken place using lyophilized plasmas as the test material. Up to 18 TEG users and 10 ROTEM users have been involved in testing two samples per study, for a total of eight samples tested. The samples were normal plasmas, factor VIII or XI deficient samples, or normal plasmas spiked with heparin. The precision of the tests varied greatly for both devices, with coefficients of variances ranging from 7.1 to 39.9% for TEG and 7.0 to 83.6% for ROTEM. Some centers returned results that were sufficiently different from those obtained by other participants to predict alterations in patient management decisions. Our data indicate that regular EQA/proficiency testing is needed for these devices.

The prevalence of lupus anticoagulant and anticardiolipin antibodies in women with a history of first trimester miscarriages

Objective To determine the prevalence of lupus anticoagulant and raised anticardiolipin antibodies in women with a history of two or more miscarriages in the first trimester of pregnancy.

The GOAL study : a prospective examination of the impact of factor V Leiden and ABO(H) blood groups on haemorrhagic and thrombotic pregnancy outcomes

Factor V Leiden (FVL) and ABO(H) blood groups are the common influences on haemostasis and retrospective studies have linked FVL with pregnancy complications. However, only one sizeable prospective examination has taken place. As a result, neither the impact of FVL in unselected subjects, any interaction with ABO(H) in pregnancy, nor the utility of screening for FVL is defined. A prospective study of 4250 unselected pregnancies was carried out. A venous thromboembolism (VTE) rate of 1·23/1000 was observed, but no significant association between FVL and pre‐eclampsia, intra‐uterine growth restriction or pregnancy loss was seen. No influence of FVL and/or ABO(H) on ante‐natal bleeding or intra‐partum or postpartum haemorrhage was observed. However, FVL was associated with birth‐weights >90th centile [odds ratio (OR) 1·81; 95% confidence interval (CI95) 1·04–3·31] and neonatal death (OR 14·79; CI95 2·71–80·74). No association with ABO(H) alone, or any interaction between ABO(H) and FVL was observed. We neither confirmed the protective effect of FVL on pregnancy‐related blood loss reported in previous smaller studies, nor did we find the increased risk of some vascular complications reported in retrospective studies.

Platelet function testing: practice among UK National External Quality Assessment Scheme for Blood Coagulation participants, 2006.

Aims: Platelet function testing forms an important part of the laboratory investigation of a bleeding tendency; however, little standardisation and quality control is available for these tests. A UK National External Quality Assessment Scheme (UK NEQAS) for Blood Coagulation exercise sought to identify current practice among laboratories performing platelet function tests. Methods: A questionnaire was circulated in March 2006 to establish the current status of platelet function testing practice among participants of UK NEQAS. Participants were asked specifically about practice in bleeding time testing, PFA-100 analyser use, platelet aggregometry methodology and additional tests of platelet function. Results: 169 returned questionnaires revealed that 26 centres used bleeding time, the PFA-100 analyser and platelet aggregometry in their investigations; 13 used bleeding time and the PFA-100 only; 33 used bleeding time and platelet aggregometry; and 23 used the PFA-100 with platelet aggregometry. 58 centres reported that they performed only bleeding times in their investigations, 10 reported use of the PFA-100 only, and 6 reported use of aggregometry only. Marked variability was observed in methodology for each of these tests, and in many cases no form of quality control was employed. Conclusions: The data confirmed the lack of standardisation in methodology employed in different centres. Updated guidelines and standardisation of platelet function assessment are required to facilitate comparability between centres.